Social Isolation, Genetic Susceptibility, Systemic Inflammation and Risk of Abdominal Aortic Aneurysm: A UK Biobank...

Abdominal aortic aneurysm (AAA) is typically asymptomatic until rupture, and established risk factors do not fully explain its occurrence. Whether social isolation, loneliness, polygenic susceptibility, and systemic inflammation jointly influence AAA risk remains unclear.

We included 356,181 White British participants from the UK Biobank free of AAA at baseline. Social isolation and loneliness indices were derived from questionnaires. A genome-wide polygenic risk score (PRS) for AAA was constructed using PRS-CS and grouped into tertiles. The systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI) were calculated from baseline blood counts. Incident AAA was identified through linked hospital, primary care, mortality, and self-report records. Cox models estimated hazard ratios (HRs), and mediation analyses quantified the proportion of the social isolation-AAA association explained by inflammatory indices.

Over 15.6 years of follow-up, 1727 AAA events occurred. A social isolation index ≥2 was associated with higher AAA risk (HR 1.23; 95% CI 1.05-1.46), and each 1-SD increase corresponded to ~11% higher risk; loneliness was not associated with AAA. Although statistical interactions were non-significant, individuals with both high PRS and high social isolation had fourfold higher risk than those with low PRS and no isolation. SIRI, but not SII, was independently associated with AAA (HR 1.24; 95% CI 1.06-1.46) and mediated ~5% of the association.

Social isolation, particularly in genetically susceptible individuals, identifies a population at substantially elevated AAA risk, partly via systemic immune-inflammatory activation, and may represent a modifiable target for prevention.